GB1575358A

GB1575358A - Benzoic acids and process for their preparation

Info

Publication number: GB1575358A
Application number: GB36527/77A
Authority: GB
Original assignee: Hoechst AG
Current assignee: Hoechst AG
Priority date: 1976-09-04
Filing date: 1977-09-01
Publication date: 1980-09-17
Also published as: ZA775333B; FR2363542A1; PT66992A; SE7709905L; AT353252B; US4182775A; PT66992B; ATA634677A; AU2855777A; NL7709584A; BE858413A; ES461971A1; JPS5331641A; FI772597A; NO773047L; DE2639935A1; CA1082717A; IL52877A0; NZ185078A; DK391677A

Description

PATENT SPECIFICATION ( 11) 1 575 358

)o ( 21) Application No 36527/77 ( 22) Filed I Sept 1977 t O ( 31) Convention Application No 2639935 19) ( 32) Filed 4 Sept 1976 in ( 33) Federal Republic of Germany (DE) " ( 44) Complete Specification published 17 Sept 1980 ( 51) INT CL 3 CO 7 C 103/84 A 61 K 31/16 31/38 C 07 D 333/38//C 07 C 63/70 101/447 121/52 ( 52) Index at acceptance C 2 C 1510200215 22022622722 Y 25425 Y 26 Y 270271 280282 29 X 29 Y 30 Y 311 313 314 31 Y 321 326 32 Y 338 339 33 X 342 34 Y 364 366 367 368 36 Y 440 451 456 45 X 45 Y 593 594 620 628 62 X 62 Y 650 65 X 665 668 688 694 697 699 776 802 80 Y AA BQ KK KM LS MC ( 54) BENZOIC ACIDS AND PROCESS FOR THEIR PREPARATION ( 71) We, HOECHST AKTIENGESELLSCHAFT, a body corporate organised according to the laws of the Federal Republic of Germany, of 6230 Frankfurt (Main) 80, Postfach 800320, Federal Republic of Germany, do hereby declare the invention for which we pray that a patent may be granted to us, and the method by which it is to be performed, to be particularly described in and by the 5

following statement:-

The present invention relates to benzoic acids and to a process for preparing them.

The present invention provides benzoic acids of the general formula I ec COI-Y Q R (') 10 R 1 co in which R represents a) a phenyl radical which is unsubstituted or is substituted by one, two or three substituents, which may be the same or different, selected from alkyl groups having from I to 3 carbon atoms, alkoxy groups having from I to 4 15 carbon atoms, alkenyloxy groups having 3 or 4 carbon atoms, CF 3 groups and halogen atoms, b) the group Ph-Z-, in which Ph represents a phenyl radical which is unsubstituted or is substituted by one or two substituents, which may be the same or different, selected from halogen atoms and alkyl and alkoxy 20 groups having from 1 to 4 carbon atoms, and Z represents a methylene group substituted by a halogen atom or an alkoxy group having from 1 to 4 carbon atoms, or represents a vinylene group or an -O alkyl or alkyl O alkyl group having from I to 4 carbon atoms in the or each alkyl moiety, 25 c) a thiophene radical which is unsubstituted or is substituted by one or two substituents, which may be the same or different, selected from alkyl groups having from 1 to 3 carbon atoms, alkoxy groups having from I to 4 carbon atoms, and halogen atoms, R' represents a hydrogen atom or an alkyl group having up to 4 carbon atoms, 30 Y represents a straight or branched chain alkylene group having from 1 to 3 carbon atoms, and R 2 represents a hydrogen or halogen atom or an alkyl group having from 1 to 4 carbon atoms.

The invention also provides the salts of the compounds of formula I, especially 35 the physiologically tolerable salts, and the esters thereof.

An alkyl or alkoxy substituent of a radical R is preferably a methyl or methoxy group, respectively, and a halogen atom is preferably a chlorine atom A CF 3 group preferably occurs only once as a substituent of a phenyl group R Of the possible meanings for R, those given under a) and b) are preferred, especially those 40 containing a chlorine-substituted phenyl group.

If R' represents an alkyl group, it is preferably a methyl group, but hydrogen is the preferred meaning for RW.

R 2 preferably represents a methyl group or a chlorine atom, especially a methyl group, and Y preferably represents a group -CH 2-CH 2-.

The invention also provides a process for the manufacture of a compound of 5 the general formula I or an ester or salt thereof, which comprises a) reacting an amine of the general formula II N-Y Q p 2 (i) R 1 cool/ in which R', R 2 and Y are as defined above, or a salt or ester thereof, with a reactive derivative of the acid RCOOH, in which R is as defined above, 10 b) in a compound of the general formula III R-CO -NY y 2 ( X in which R, R', R 2 and Y are as defined above and X represents a radical convertible into a carboxyl group, by hydrolysis or oxidation, converting that radical into a carboxyl group, 15 c) to prepare a compound of the general formula I, in which the radical R contains an alkoxy group, alkylating the corresponding hydroxy compound, and, if desired, d) converting a resulting free acid into an ester or salt, e) converting a resulting ester into another ester, the free acid, or a salt, or 20 f) converting a resulting salt into another salt, the free acid, or an ester.

For the preparation according to process a) there may be used as the reactive derivative of the acid RCOOH an acid halide, anhydride, mixed anhydride, ester or azide, preferably an acid chloride or a mixed anhydride The compound of formula II may be used in the form of the free acid or an ester or salt thereof, the salts being 25 not only salts of the carboxyl group with bases but also those of the amine group with acids The reaction may be carried out in water, an organic solvent, or a mixture of any two or more solvents selected from water and organic solvents, and in the presence of an inorganic or organic base.

According to process b) the radical X may be converted into a carboxyl group 30 by hydrolysis or by oxidation A radical which can be converted hydrolytically into a carboxyl group is, for example, a nitrile group, an amide group or an iminoether group, an iminoether group possibly also being converted directly into an ester group By oxidation, for example, a hydroxymethyl, aminomethyl, formyl or acyl group may be converted into a carboxyl group by the action of an oxidising agent, 35 for example, permanganate, chromate or hypochlorite, silver oxide or atmospheric oxygen.

For the preparation according to process c) the hydroxy compound is reacted with an alkylating agent, for example, an alkyl halide or dialkyl sulphate.

The compounds of the invention may be converted into salts, especially 40 physiologically tolerable salts, for example, alkali metal salts, alkaline earth metal salts and salts with appropriate amines The preparation of these salts is effected, for example, by reaction with a free base or carbonate.

A benzoic acid may also be converted into an ester, using in principle, any alcohol, but preferably a lower alcohol, for example, methanol, ethanol, or 45 propanol, or glycol, ethanolamine or a glycol ether.

The compounds of the invention have useful therapeutic properties and are distinguished by a lipid lowering action.

Various benzoic acids having a lipid lowering and hypoglycaemic action have already been described in laterature, for example, phenoxyalkyl-benzoic acids and 50 phenylalkoxybenzoic acids, cf German Offenlegungsschrift No 2,439,458 It was surprising, however, that the acylaminoalkylbenzoic acids of the invention also show a pronounced lipid lowering action.

The lipid lowering action can be determined in various test models In the 1.575,358 standard test, male rats having a normal serum lipid content are given the preparation orally for 8 days at a dosage of 100 mg/kg by means of an oesophageal sound.

Blood is withdrawn before and after the treatment, the concentration of cholesterol in the serum is determined according to the method of Lauber and 5 Richterich, and the triglycerides are determined according the method of Eggstein and Kreutz The values obtained are compared with the starting concentrations and also with a control group.

Some of the compounds also show a hypoglycaemic action which can, for example be evaluated in the test model described above, by determining the blood 10 sugar concentration before and after the treatment according to the method of Hagedorn-Jensen in an autoanalyser or according to the hexokinase method The hypoglycaemic effect may also be evaluated by administering the preparations in doses of 100 mg/kg to normally fed rabbits and determining the blood sugar over a longer period of time according to one of the above mentioned methods 15 The invention accordingly provides a pharmaceutical preparation which comprises, as the active ingredient, a compound of the general formula I or an ester or physiologically tolerable salt thereof, or a compound of the general formula I together with a substance with which said compound is capable of forming a physiologically tolerable salt, in admixture or conjunction with a pharmaceutically 20 suitable carrier These preparations have a lipid lowering action and are therefore suitable for the treatment of lipidosis and/or diabetes mellitus They are preferably in a form suitable for oral administration, for example, tablets, in which the carrier is, for example, talc, starch, lactose, tragacanth, or magnesium stearate.

The preparation is preferably in unit dosage form The dose will vary 25 according to the effectiveness of the active substance used and the desired effect, but is generally in the range of from 0 1 to 2 g, preferably from 0 5 to 1 g Use may also be made of higher or lower dosage units which are optionally to be divided or multiplied prior to their application.

The pharmaceutical preparations of the invention may comprise one or more 30 further therapeutically active substances, for example, circulatory preparations in the broadest sense, especially agents capable of dilating the coronary vessels, for example, chromonar and prenylamin, and antihypertensive agents, for example, reserpine, a methyl dopa and calonidine, other antihyperlipidemic agents, geriatric agents, psychopharmacological agents, for example, chlorodiazepoxide, 35 diazepam or meprobamate, and vitamins For the treatment of diabetes militus there may be included in the pharmaceutical preparation one or more other hypoglycaemic sulphonyl ureas and/or compound of a different chemical structure, for example, biguanides, especially phenylethyl biguanide or dimethyl biguanide.

The following Examples illustrate the invention 40 EXAMPLE 1 ( 3 chloro benzamido methyl) 2 methyl benzoic Acid millilitres of 2 N sodium hydroxide solution are added to 4 g of 5 (aminomethyl) 2 methyl benzoic acid HCI (melting point 232 to 2400 C (decomp), prepared by reacting 5 (chloromethyl) 2 methyl benzoic acid 45 with hexamethylene tetramine and separating the reaction product with hydrochloric acid) in 30 ml of acetone.

Then 3 5 g of 3 chlorobenzoyl chloride in a small amount of acetone are added dropwise, while stirring and cooling with ice, the mixture is stirred for further 2 hours at room temperature, the precipitated substance is dissolved with 50 diluted ammonia, is filtered while adding charcoal, and the filtrate is acidified The precipitated 5 ( 3 chloro benzamido methyl) 2 methyl benzoic acid is dissolved and recrystallized from diluted methanol and melts at a temperature in the range of from 207 to 2090 C.

In an analogous manner there is obtained: 55 ( 4 chloro benzamido methyl) 2 methyl benzoic acid, melting point 205 to 2070 C (from diluted methanol), ( 5 chloro 2 methoxy benzamido methyl) 2 methyl benzoic acid, melting point 183 to 185 C (from diluted methanol), and 5 ( 2,5 dichloro benzamido methyl) 2 methyl benzoic acid, melting 60 point 215 to 217 C (from diluted methanol).

I 1,575,358 EXAMPLE 2 ( 2 l 4 chloro benzamidol ethyl) 2 methyl benzoic Acid a) 5 ( 2 amino ethyl) 2 methyl benzoic acid:

34.6 grams of 5 cyanomethyl 2 methyl benzoic acid (melting point 158 to 160 C, prepared from 5 chloromethyl 2 methyl benzoic acid and 5 potassium cyanide) are hydrogenated in 700 ml of methanol in the presence of 300 ml of 10 , sodium hydroxide solution and Raney nickel at 70 C and 100 atmospheres gauge of hydrogen After cooling, the methanol is distilled off, the residue is acidified with concentrated hydrochloric acid and evaporated The residue is boiled out with methanol, the methanolic solution is evaporated, the 10 hydrochloride obtained is treated with acetone Melting point 264 to 266 C (decomp).

b) 5 ( 2 l 4 chloro benzamidol ethyl) 2 methyl benzoic Acid 13 grams of 5 ( 2 aminoethyl) 2 methyl benzoic acid x HCI are dissolved in 70 ml of acetone and 90 ml of 2 N sodium hydroxide solution 10 5 15 grams of 4 chlorobenzoyl chloride in 20 ml of acetone are added dropwise, while stirring and cooling with ice, then the mixture is continued to be stirred for 2 hours at room temperature, the acetone is removed under reduced pressure, the residue is reprecipitated from diluted ammonia and recrystallized from diluted methanol.

The 5 ( 2 l 4 chloro benzamidol ethyl) 2 methyl benzoic acid 20 obtained melts at a temperature in the range of from 216 to 218 C.

In an analogous manner, the following compounds are obtained:

( 2 < 3 chloro benzamido> ethyl) 2 methyl benzoic acid, m p.

178 to 180 C (from diluted methanol); 5 ( 2 ( 4 methyl benzamido> ethyl) 2 methyl benzoic acid, m p 25 211 to 213 C (from diluted methanol); ( 2 ( 4 methoxy benzamido) ethyl) 2 methyl benzoic acid, m p.

212 to 213 C (from diluted methanol); ( 2 ( 2 methoxy benzamido) ethyl) 2 methyl benzoic acid, m p.

158 to 160 C (from diluted methanol); 30 ( 2 ( 4 bromo benzamido) ethyl) 2 methyl benzoic acid, m p.

231 to 233 C (from diluted methanol); ( 2 ( 5 chloro 2 methoxy benzamido) ethyl) 2 methyl benzoic acid, m p 150 to 152 C (from diluted methanol); 5 ( 2 ( 4 chloro 2 methoxy benzamido) ethyl) 2 methyl 35 benzoic acid, m p 152 to 154 C (from diluted methanol); ( 2 ( 5 chloro 2 ethoxy benzamido) ethyl) 2 methyl benzoic acid, m p 144 to 146 C (from diluted methanol); ( 2 ( 4 chloro 2 ethoxy benzamido) ethyl) 2 methyl benzoic acid, m p 136 to 138 C (from diluted methanol); 40 ( 2 ( 4 chloro 2 N propyloxy benzamido> ethyl) 2 methyl benzoic acid, m p 133 to 135 C (from diluted methanol); ( 2 ( 5 chloro 2 N butoxy benzamido) ethyl) 2 methyl benzoic acid, m p 137 to 139 C (from diluted methanol); 5 ( 2 ( 4 chloro 2 N butoxy benzamido) ethyl) 2 methyl 45 benzoic acid, m p 130 to 132 C (from diluted methanol); ( 2 ( 2 allyloxy 5 chloro benzamido) ethyl) 2 methyl benzoic acid, m p 114 to 115 C (from diluted methanol); ( 2 ( 5 methyl 2 methoxy benzamido> ethyl) 2 methyl benzoic acid, m p 127 to 129 C (from diluted methanol); 50 ( 2 ( 4 chloro 2 methyl benzamido> ethyl) 2 methyl benzoic acid, m p 184 to 186 C (from diluted methanol); ( 2 ( 3 chloro 4 methyl benzamidoj ethyl) 2 methyl benzoic acid, m p 194 to 196 C (from diluted methanol); 5 ( 2 ( 3,4 dichloro benzamido) ethyl) 2 methyl benzoic acid, 55 m.p 205 to 207 C (from diluted methanol); ( 2 ( 3,5 dichloro benzamido) ethyl) 2 methyl benzoic acid, m.p 222 to 224 C (from diluted methanol); ( 2 ( 2,4,5trimethoxy benzamido> ethyl) 2 methyl benzoic acid, m p 220 to 222 C (from ethanol); 60 ( 2 ( 2,5 dichloro benzamido) ethyl) 2 methyl benzoic acid, m.p 222 to 224 C (from methanol/dioxan); ( 2 ( 2,4 dichloro benzamido) ethyl) 2 methyl benzoic acid, m.p 183 to 185 C (from diluted methanol); 1,575,358 ( 2 ( 3 methyl benzamido) ethyl) 2 methyl benzoic acid, m p.

to 187 C (from diluted methanol); ( 2 ( 2 chloro 5 methyl benzamido) ethyl) 2 methyl benzoic acid, m p 204 to 206 C (from diluted methanol); 2 methyl 5 ( 2 ( 3 trifluoromethyl benzamido) ethyl) benzoic 5 acid, m p 163 to 165 C (from diluted methanol); 2 methyl S ( 2 ( 4 trifluoromethyl benzamido) ethyl) benzoic acid, m p 201 to 202 C (from diluted methanol); ( 2 ( 2,4 dimethyl benzamido) ethyl) 2 methyl benzoic acid, m p 193 to 195 C (from diluted ethanol); 10 ( 2 ( 5 chloro thiophene 2 carboxamido) ethyl) 2 methyl benzoic acid, m p 175 to 177 C (from diluted methanol); ( 2 ( 3,5 dichloro 2 methoxy benzamido) ethyl) 2 methyl benzoic acid, m p 116 to 118 C (from ethanol); 5 2 ( 2,4,5 trichloro benzamido> ethyl) 2 methyl benzoic acid, 15 m.p 224 to 226 C (from ethanol); ( 2 ( 4 fluoro benzamido) ethyl) 2 methyl benzoic acid, m p.

to 177 C (from diluted ethanol); ( 2 ( 3 fluoro benzamido) ethyl) 2 methyl benzoic acid, m p.

205 to 207 C (from diluted methanol); 20 ( 2 ( 2 methoxy 2 phenyl acetamido> ethyl) 2 methylbenzoic acid, m p 126 to 127 C (from diluted methanol); ( 2 ( 2 ( 4 chlorophenyl) 2 methoxy acetamido) ethyl) 2 methyl benzoic acid, m p 142 to 143 C (from diluted methanol); 5 ( 2 cinnamoylamino ethyl) 2 methyl benzoic acid, m p 213 to 25 215 C (from isopropanol); S ( 2 ( 4 chloro cinnamoylamino) ethyl) 2 methyl benzoic acid, m.p 217 to 219 C (from methanol); ( 2 ( 2,4 bichloro cinnamoylamino> ethyl) 2 methyl benzoic acid, m p 209 to 211 C (from diluted methanol); 30 S ( 2 phenoxyacetamido ethyl) 2 methyl benzoic acid, m p 144 to 146 C (from diluted methanol); S ( 2 ( 4 chloro phenoxyacetamido) ethyl) 2 methyl benzoic acid, m.p 176 to 178 C (from diluted methanol).

EXAMPLE 3 35

2 chloro 5 ( 2 l 5 chloro 2 methoxy benzamidol ethyl) benzoic Acid 2.5 grams of 2 chloro 5 ( 2 aminoethyl) benzoic acid, HC 1 (melt point 264 to 268 C, prepared by the bromination of 2 chloro 5 methyl benzoic acid, reaction of the bromide with potassium cyanide to give the nitrile, m p 140 to 40 143 C, and catalytic hydrogenation of the nitrile to give the amine) are mixed with the solution of 0 8 g of sodium hydroxide in 30 ml of water, then 2 1 g of 5 chloro 2 methoxy benzoyl chloride in 30 ml of acetone are added dropwise to the mixture, while stirring and cooling, subsequently the mixture is continued to be stirred for 1 hour at room temperature, is acidifed with diluted hydrochloric acid, 45 then it is suction-filtered, the precipitate is reprecipitated from diluted ammonia and recrystallized from diluted methanol The 2 chloro 5 ( 2 l 5 chloro 2 methoxy benzamidol ethyl) benzoic acid obtained melts at a temperature in the range of from 172 to 174 C.

In an analogous manner, the following products are obtained: 50 2 chloro 5 ( 2 ( 2 ethoxy 5 chloro benzamido> ethyl) benzoic acid, m p 147 to 150 C (from diluted methanol); 2 chloro 5 ( 2 ( 2 N butoxy 5 chloro benzamido> ethyl) benzoic acid, m p 154 to 157 C (from diluted methanol); 2 chloro 5 ( 2 ( 2 allyloxy 5 chloro benzamido) ethyl) benzoic 55 acid, m p 145 to 147 C (from diluted methanol); 2 chloro 5 ( 2 ( 2 methoxy benzamido) ethyl) benzoic acid, m p.

148 to 150 C (from diluted methanol); 2 chloro 5 ( 2 ( 4 chloro benzamido) ethyl) benzoic acid, m p.

150 to 152 C (from diluted methanol) 6 C EXAMPLE 4

2 chloro 5 ( 4 chloro benzamidomethyl) benzoic Acid 4.4 grams of 2 chloro 5 (aminomethyl) benzoic acidx HC 1 (m p 220 to 1,575,358 230 C (decomp), prepared by reacting 5 bromomethyl 2 chloro benzoic acid with hexamethylene tetramine and splitting off the reaction product with hydrochloric acid) in 40 ml of acetone are mixed with the solution of 1 7 g of sodium hydroxide in 20 ml of water The mixed anhydride prepared from 3 2 g of 4 chloro benzoic acid, 2 5 g of triethylamine, and 2 3 g of chloroformic acid 5 methylester in 50 ml of acetone is added dropwise, while stirring and cooling, and the whole is continued to be stirred for 2 hours at room temperature.

Subsequently the acetone is removed under reduced pressure, the residue is mixed with diluted hydrochloric acid, is filtered off with suction and the product obtained is dissolved and recrystallized from diluted methanol The 2 chloro 5 10 ( 4 chloro benzamidomethyl) benzoic acid obtained melts at a temperature in the range of from 195 to 197 C.

In an analogous manner, 2 chloro 5 ( 5 chloro 2 methoxy benzamidomethyl) benzoic acid is obtained, which has a m p in the range of from 196 to 197 C (from dil methanol), 15 EXAMPLE 5

3 ( 2 l 4 chloro benzamidol ethyl) benzoic Acid 4.1 grams of 3 ( 2 amino ethyl) benzoic acidx HCI (prepared by the bromination of 3 methyl benzoic acid, reaction of the bromide, m p 147 to 149 C, with potassium cyanide to give the nitrile, m p 175 to 178 C, and 20 hydrogenation of the nitrile to give the amine) in 30 ml of acetone are mixed with ml of 2 N sodium hydroxide solution 3 5 grams of 4 chlorobenzoyl chloride in ml of acetone are added dropwise to the mixture, while stirring and cooling, said mixture is then continued to be stirred for 2 hours at room temperature, the acetone is distilled off for the most part under reduced pressure, the residue is 25 acidified, is filtered off with suction and recrystallized from diluted methanol The 3 ( 2 l 4 chloro benzamidol ethyl) benzoic acid obtained melts at a temperature in the range of from 205 to 208 C.

EXAMPLE 6

5 ( 2 l 4 chloro benzamidol ethyl) 2 methyl benzoic acid ethylester 30 6 grams of 5 ( 2 l 4 chloro benzamidol ethyl) 2 methyl benzoic acid in 50 ml of ethanol are boiled for 4 hours with 1 5 ml of concentrated sulfuric acid under reflux Subsequently the alcohol is distilled off for the most part, the residue is mixed with ice, the precipitate is filtered off with suction, is treated with diluted ammonia in order to remove the acid still present and is recrystallized from 35 diluted ethanol.

The 5 ( 2 l 4 chloro benzamidol ethyl) 2 methyl benzoic acid ethylester obtained melts at a temperature in the range of from 116 to 118 C.

EXAMPLE 7

5 ( 2 l 4 chloro benzamidol 1 methyl ethyl) 2 methyl benzoic Acid 40 6.7 grams of 5 ( 2 amino 1 methyl ethyl) 2 methyl benzoic acid in the form of the hydrochloride (m p 236 to 238 C, obtained by reaction of the 5 cyanomethyl 2 methyl benzoic acid methylester with diethylcarbonate and sodium alcoholate, methylation of the compound obtained with methyl iodide, separation of the carbethoxy group and hydrogenation of the nitrile) are dissolved 45 with 45 ml of 2 N sodium hydroxide solution and 40 ml of acetone and are reacted with 5 3 g of 4 chlorobenzoyl chloride in a small amount of acetone, while stirring and cooling with ice The mixture is continued to be stirred for 2 hours at room temperature, the acetone is removed under reduced pressure, and the residue is acidified The precipitated acid is filtered off with suction, is reprecipitated from 50 ammonia and recrystallized from methanol The 5 ( 2 l 4 chloro benzamidol 1 methyl ethyl) 2 methyl benzoic acid obtained melts at a temperature of from 188 to 189 C.

Claims

WHAT WE CLAIM IS:-

1 A benzoic acid of the general formula I 55 0-co-N-Y O R 2) R 1 coo H/ 1,575,358 in which R represents a) a phenyl radical which is unsubstituted or is substituted by one, two or three substituents, which may be the same or different, selected from alkyl groups having from 1 to 3 carbon atoms, alkoxy groups having from I to 4 5 carbon atoms, alkenyloxy groups having 3 or 4 carbon atoms, CF 3 groups and halogen atoms, b) the group Ph-Z-, in which Ph represents a phenyl radical which is unsubstituted or is substituted by one or two substituents, which may be the same or different, selected from halogen atoms and alkyl and alkoxy 10 groups having from 1 to 4 carbon atoms, and Z represents a methylene group substituted by a halogen atom or an alkoxy group having from 1 to 4 carbon atoms, or represents a vinylene group or an -o alkyl or alkyl 0 alkyl group having from 1 to 4 carbon atoms, in the or each alkyl moiety, 15 c) a thiophene radical which is unsubstituted or is substituted by one or two substituents, which may be the same or different, selected from alkyl groups having from 1 to 3 carbon atoms, alkoxy groups having from I to 4 carbon atoms, and halogen atoms, R' represents a hydrogen atom or an alkyl group having up to 4 carbon atoms, 20 Y represents a straight or branched chain alkylene group having from 1 to 3 carbon atoms, and R 2 represents a hydrogen or halogen atom or an alkyl group having from 1 to 4 carbon atoms.

2 A compound as claimed in Claim 1, wherein an alkyl or alkoxy substitutent 25 of a radical R is a methyl or methoxy group, respectively, and a halogen substituent is a chlorine atom.

3 A compound as claimed in Claim 1, wherein R represents a chlorinesubstituted phenyl group.

4 A compound as claimed in any one of Claims 1 to 3, wherein R 2 represents a 30 methyl group or a chlorine atom.

A compound as claimed in any one of Claims 1 to 4, wherein Y represents an ethylene group.

6 A compound as claimed in Claim 1, substantially as described in any one of Examples 1 to 5 and

7 herein 35 7 An ester of a compound as claimed in any one of Claims I to 6.

8 A salt of a compound as claimed in any one of Claims I to 6.

9 A physiologically tolerable salt of a compound as claimed in any one of Claims 1 to 6.

10 A process for the preparation of a compound as claimed in Claim I or an 40 ester or salt thereof, which comprises a) reacting an amine of the general formula

II A'N -Y O ( 2 in which Y, R' and R 2 are as defined in Claim 1, or a salt or ester thereof, with a reactive derivative of the acid RCOOH, in which R is as defined in Claim 1, 45 b) in a compound of the general formula III R-CO-N-Y O F ('ii R 1 x RI X in which R, RI, R 2 and Y are as defined in Claim 1 and X represents a radical convertible into a carboxyl group by hydrolysis or oxidation, converting that radical into a carboxyl group, 50 c) to prepare a compound of the general formula I, in which the radical R contains an alkoxy group, alkylating the corresponding hydroxy compound, and, if desired, d) converting a resulting free acid into an ester or salt, e) converting a resulting ester into another ester, the free acid, or a salt, or 55 f) converting a resulting salt into another salt, the free acid, or an ester.

I 1,575,358 11 A process as claimed in Claim 10, carried out substantially as described in any one of the Examples herein.

12 A compound as claimed in Claim 1, or an ester or salt thereof, whenever prepared by a process as claimed in Claim 10 or Claim 11.

13 A pharmaceutical preparation which comprises, as active ingredient, a 5 compound of formula I as claimed in any one of Claims 1 to 6, or Claim 12, or an ester or a physiologically tolerable salt thereof, or a compound of formula I as claimed in any one of Claims 1 to 6 or Claim 12 in the presence of a substance with which said compound is capable of forming a physiologically tolerable salt, in admixture or conjunction with a pharmaceutically suitable carrier 10

14 A pharmaceutical preparation as claimed in Claim 13, in a form suitable for oral administration.

A pharmaceutical preparation as claimed in Claim 14, in unit dosage form.

16 A pharmaceutical preparation as claimed in Claim 15, which comprises from 0 1 to 2 g of the active ingredient per unit dose 15

17 A pharmaceutical preparation as claimed in Claim 16, which comprises from 0 5 to 1 g of the active ingredient per unit dose.

18 A pharmaceutical preparation as claimed in any one of Claims 13 to 17, which comprises one or more further therapeutically active substances.

ABEL & IMRAY, Chartered Patent Agents, Northumberland House, 303-306 High Holborn, London WC 1 V 7 LH.

Printed for Her Majesty's Stationery Office, by the Courier Press, Leamington Spa, 1980 Published by The Patent Office, 25 Southampton Buildings, London, WC 2 A IAY, from which copies may be obtained.

1,575,358